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Design of selective nuclear receptor modulators: RAR and RXR as a case study

Nature Reviews Drug Discovery volume 6, pages 811–820 (2007)Cite this article

Key Points

  • Small-molecule ligands that modulate the action of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) — members of the nuclear receptor superfamily — have been used as anticancer drugs. However, their use can be limited by side effects.

  • RARs and RXRs are each expressed from three isotypic genes (α,β and γ). The receptors are composed of a modular structure with several domains and associated functions. The main domains are the DNA-binding domain (DBD) and the ligand-binding domain (LBD).

  • Drug discovery efforts are focusing on isotype-selective modulators to reduce toxicity associated with current retinoid therapy; elicit more specific biological responses, because the tissue distribution of retinoid receptor isotypes is not uniform; better define the physiological role of each retinoid receptor isotype; and clarify the potential of RXR-targeted pharmacology.

  • Various crystal structures of RARs and RXRs have been elucidated, allowing for the correlation of ligand structure and (allosterically altered) receptor structure with the functional properties of the ligand-bound receptor.

  • This information will provide guidelines for the design of novel analogues, and advances in synthetic organic chemistry will also be useful in the development of isotype-selective ligands with a range of activities from agonists to inverse agonists through to powerful antagonists.

Abstract

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-molecule ligands. Although compounds that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biology of RXRs and RARs and recent advances in the chemical synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, we review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.

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Figure 1: Structural and functional organization of retinoid receptors.
Figure 2: Agonist-induced conformational change and RXR activation.
Figure 3: Structural features of full and partial ligand-dependent AF-2 antagonism.
Figure 4: Modulation of RAR–RXR communication by ligands.
Figure 5: Retinoids, arotinoids and retinoid-related molecules.
Figure 6: Structural basis of RAR isotype and RXR ligand selectivity.

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Acknowledgements

We thank Adán González for his help in preparing the movies and all the members of our laboratories for their contributions to, and discussions of the work described. Work in our laboratories is supported by grants from the European Union QLK3-CT2002-02029 and EPITRON LSHC-CT2005-518417 (L.A., A.R. de L., H.G.); the VINCI program and the Association pour la Recherche sur le Cancer (L.A., H.G.); the Ministero dell'Istruzione, Università e Ricerca (PRIN 2006052835_003) and la Regione Campania L.S. annualità 2005; SAF2004-07131-FEDER (to A.R. de L.); the Ligue contre le Cancer (équipe labelisé), the Institut National de Cancer, the Association for International Cancer Research (AICR) and the European Union grants CRESCENDO LSHM-CT2005-018652 and X-TRA-NET LSHG-CT2005-018882 (H.G.).

Author information

Authors and Affiliations

  1. Departamento de Quimica Org´nica, Universidade de Vigo, Facultad de Quimica, Vigo, 36310, Spain

    Angel R. de Lera

  2. INSERM, U554, Montpellier, 34090, France

    William Bourguet

  3. Université Montpellier 1 et 2, CNRS, UMR5048, Centre de Biochimie Structurale, Montpellier, 34090, France

    William Bourguet

  4. Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico Luigi de Crecchio 7, Napoli, 80138, Italy

    Lucia Altucci

  5. Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, Illkirch Cedex, 67404, France

    Hinrich Gronemeyer

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  1. Angel R. de Lera
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Correspondence to Hinrich Gronemeyer.

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Supplementary information

Supplementary information S1 (table)

Crystal structures of apo- and holo-retinoid receptors (PDF 438 kb)

Supplementary information S2 (movie)

Activation of RXR by a rexinoid and the mouse-trap mechanism (GIF 6232 kb)

Supplementary information S3 (movie)

Mechanism of antagonistic action in RAR (GIF 3746 kb)

Supplementary information S4 (box)

Structure of selective retinoids, rexinoids and RXR modulators. (PDF 141 kb)

Supplementary information S5 (box)

Hydrophobic, linker and polar motifs for retinoid build-up. (PDF 168 kb)

Supplementary information S6 (box)

Hydrophobic, linker and polar motifs for rexinoid build-up (PDF 159 kb)

Supplementary information S7 (table)

Atypical retinoids and retinoid-related molecules (RRMs) (PDF 306 kb)

Supplementary information S8 (box)

Enantioselective synthesis of BMS270,394 (PDF 132 kb)

Supplementary information S9 (box)

Enantioselective synthesis of AGN194,204 (PDF 131 kb)

Supplementary information S10 (movie)

Isotype specificity of RAR ligand-binding domains (GIF 6482 kb)

Supplementary information S11 (table)

Selective RXR modulators (PDF 194 kb)

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Nuclear Receptor Signaling Atlas

Nuclear Receptor Database

Glossary

Agonist

An endogenous substance or a drug that can interact with a receptor and initiate a physiological or a pharmacological response characteristic of that receptor.

Antagonist

A drug or a compound that opposes the physiological effect of another. At the receptor level, it is a chemical entity that opposes the receptor-associated response normally induced by another bioactive agent.

Co-activators

(CoAs). Proteins that cooperate with nuclear hormone receptors to activate transcription. Two classes are known: the p160 family, which recruits histone acetyltransferases, and the TRAP–DRIP–SMCC complex, which is thought to interact with the basal transcription machinery.

Co-repressors

(CoRs). Proteins that cooperate with nuclear hormone receptors to repress transcription. CoRs tether histone deacetylase-containing complexes to target gene promoters. The two main nuclear receptor CoRs are nuclear receptor CoRs and silencing mediator of retinoid and thyroid hormone receptors.

Selective nuclear receptor modulators

(SNuRMs). Ligands that selectively modulate different receptor isotypes and/or act in a cell-selective manner. Note that the term is used in a broader context than for the oestrogen receptors (SERMs) to include receptor isotype selectivity, RAR/RXR selectivity and cell-selective functionality (for example, agonist or antagonist action) of NR ligands.

Teratogenicity

Teratogenicity is when a substance (teratogen) produces a malformation in an embryo.

Partial agonist

An agonist that is unable to induce maximal activation of a receptor population, regardless of the amount of drug applied.

Inverse agonist

A ligand that stabilizes an inactive conformation of a receptor, for example, by increasing co-repressor interaction, thereby decreasing signalling below basal levels.

Analogue

An analogue is a drug that has a structure that is related to that of another drug but whose chemical and biological properties may be quite different.

Pan-agonist

A ligand that activates all isotypes of a receptor (for example, retinoic acid receptor-α (RARα), RARβ and RARγ) similarly.

Trans-activation

Activation of transcription by the binding of a transcription factor to a DNA-regulatory sequence.

Transcriptomics

Technology by which the expression of a large number of genes, or of the entire genome, are monitored.

ChIP-on-chip

Immunoprecipitated DNA from a chromatin immunoprecipitation (ChIP) experiment is amplified, labelled and used as a probe to interrogate the entire genome, spotted as 'tiling arrays' on chips, for binding sites or chromatin modifications. These tiling arrays cover the entire genome as precisely defined consecutive arrays of oligonucleotides.

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de Lera, A., Bourguet, W., Altucci, L. et al. Design of selective nuclear receptor modulators: RAR and RXR as a case study. Nat Rev Drug Discov 6, 811–820 (2007). https://doi.org/10.1038/nrd2398

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